Lactose is a core structural unit of many complex carbohydrates including the globo series of tumor associated carbohydrate antigens (TACAs). Globotriaosyl ceramide (Gb3), Gb5, and Globo-H all share the structural feature resulting from galactosylation of the 4′ hydroxyl of lactose giving rise to Pk trisaccharide (FIG. 1). The carbohydrate backbone of Pk trisaccharide has attracted the attention of synthetic chemists since most, if not all, syntheses of the globo series intercept variously protected versions of the trisaccharide at some point during the synthesis. Nicolaou and co-workers were the first to report the synthesis of Gb3, and their approach remains one of the most efficient to date. A total of eleven steps (from commercially available lactose) were required to prepare a protected version of Pk trisaccharide that served as a donor for the ceramide aglycone. Seven of those steps were focused on orthogonally protecting lactose for 4′ galactosylation. In fact, all previously reported chemical syntheses of Pk trisaccharide require between 6-12 steps to prepare the lactosyl acceptor.
Recently, the present inventors demonstrated that per-O-silylated monosaccharides undergo regioselective exchange of silicon for acyl protecting groups providing useful building blocks for organic synthesis in a single step. This process not only results in the generation of orthogonally protected carbohydrates, but also circumvents the well-documented problem of trans-acetylation associated with partially acylated pyranosides. While selective acetylation of the primary C-6 hydroxyl of alkyl glycosides has been demonstrated, preferential modification of other hydroxyl groups is more challenging. Unfunctionalized carbohydrates have proven even more difficult to selectively modify, as they can exhibit anomalous behaviour. As opposed to using either alkyl glycosides or unfunctionalized sugars, the present invention is based on the selective exchange of silyl ether moieties in protected disaccharides with acyl moieties. Surprisingly, the exchange can be achieved under conditions that would otherwise have been expected to result in glycosidic cleavage of the disaccharide substrates. This extraordinary reactivity allows for the rapid preparation of carbohydrate derivatives such as orthogonally 4′-protected lactose, which can be readily transformed into Pk trisaccharide. As such, the invention meets a long-standing need for synthetic intermediates that can be used for the preparation of biologically and industrially important carbohydrate compounds.